Journal of Clinical Endocrinology & Metabolism最新文献

Context: A preclinical state of Graves' ophthalmopathy (pre-GO) exists during the progression from Graves' hyperthyroidism (GH) to GO.

Objective: To distinguish the pre-GO state and identify key pathways of T-cell immunity.

Methods: Twenty-four GH (without ophthalmopathy within 6-month follow-up), 10 pre-GO (ophthalmopathy occurred within 6-month follow-up), and 21 GO patients were enrolled, and the transcription and DNA methylation profiles of peripheral blood mononuclear cells were generated. The differentially expressed genes (DEGs), differentially methylated CpG sites (DMCs), and differentially methylated genes (DMGs) were identified. Cluster analysis, functional analysis, and data integration analysis using latent components (DIABLO) were performed to distinguish pre-GO and identify key pathways. Flow cytometry was performed for in vitro verification.

Results: In total, 731, 1214, and 372 DEGs and 1583, 277, and 555 DMCs were detected via pairwise comparisons of GH vs GO, pre-GO vs GO, and GH vs pre-GO, respectively. DIABLO accurately discriminated the pre-GO state via 17 DMC and 11 DEG features ( receiver operating characteristic = 0.9975 and 0.9407, respectively). The functional analysis revealed that the DMGs and DEGs were enriched in T-cell differentiation pathways and related cytokine pathways, respectively. Further cluster analysis revealed a cluster of pre-GO-specific DEGs enriched in the hypoxia pathway. Flow cytometry confirmed that hypoxia promoted Th1, Th17, and antigen-specific CD4+ cytotoxic T-cell differentiation.

Conclusion: The pre-GO state was identified from GH and GO and characterized by upregulation of the hypoxia pathway that may promote effector CD4+ T-cells differentiation. These findings provide new insight into the pathogenesis and prevention of GO.

Context: 47,XXY/Klinefelter syndrome (XXY) is associated with impaired testicular function and differences in physical growth, metabolism, and neurodevelopment. Clinical features of XXY may be influenced by testosterone during the minipuberty period of infancy.

Objective: We tested the hypothesis that exogenous testosterone treatment positively affects short-term physical, hormonal, and neurodevelopmental outcomes in infants with XXY.

Design: Double-blind randomized controlled trial, 2017-2021.

Setting: US tertiary care pediatric hospital.

Patients: Infants 30 to 90 days of age with prenatally identified, nonmosaic 47,XXY (n = 71).

Intervention: Testosterone cypionate 25 mg IM injections every 4 weeks for 3 doses.

Main outcome measures: The a priori primary outcomes were change in percent fat mass z-scores and change in the total composite percentile on Alberta Infant Motor Scales assessment from baseline to 12 weeks.

Results: The between-group difference in change in percent fat mass z-scores was -0.57 (95% CI, -1.1 to -0.06; P = .03), secondary to greater increases in lean mass in the testosterone-treated group (1.5 ± 0.4 kg vs 1.2 ± 0.4; P = .001). Testosterone suppressed gonadotropins and inhibin B (P < .001 for all). In contrast, there were no significant group differences in short-term motor, cognitive, or language outcomes (P > .15 for all).

Conclusions: In this double-blind randomized controlled trial in infants with XXY, testosterone injections resulted in physical effects attributable to systemic androgen exposure; however, this dose suppressed the hypothalamic-pituitary-gonadal axis. Neurodevelopment outcomes were not impacted by treatment. These results do not support routine testosterone treatment in infants with XXY; however, long-term follow-up on physical health, neurodevelopment, and testicular function is needed.

Context: Increasing evidence supports the presence of oxytocin deficiency (OXT-D) in hypopituitarism and hypothalamic damage (HHD). Identifying an applicable and reliable test to diagnose OXT-D is an unmet need. Melatonin (MEL) might be a candidate for such a test as it regulates OXT release in animals.

Objective: This work aimed to examine the effects of melatonin on OXT release in HHD compared to healthy controls (HCs) and to describe the psychopathology, sexual function, and quality of life (QoL) and their associations with OXT.

Methods: This proof-of-concept study (NCT05319301) included 20 participants with HHD (11 women) and 20 HCs (11 women). Blood samples were collected over 120 minutes to assess plasma OXT. A linear mixed-effects regression model was used to evaluate the change in OXT in response to MEL in HHD compared to HCs.

Results: MEL significantly increased OXT at T90 vs T0 in HCs compared to the HHD group (difference 14.57 pg/mL 26% increase; 95% CI, 1.90-27.23; P = .02). The HHD group had more depression symptoms, alexithymia, impaired sexual function, and worse QoL compared to HCs. The mean percentage change in OXT from T0 to T90 was negatively associated with depressive and alexithymia symptoms in the HHD group and anxiety in both groups.

Conclusion: The reduced OXT response after MEL in HHD supports the existence of an impaired OXT response at least in a subset of patients with HHD. The associations between OXT changes and psychopathology suggest its role in mood and QoL. These findings support further investigation into MEL's role as a diagnostic tool to address OXT-D.

Context: The transformation of follicular granulosa cells into luteal cells of the corpus luteum remains poorly understood in the human ovary.

Objective: To investigate the luteinization process and steroidogenic differences between granulosa cells from small antral and preovulatory follicles in vitro.

Methods: At the University Hospital of Copenhagen, Denmark, and Wake Forest Institute for Regenerative Medicine, USA, granulosa-lutein cells were obtained from 12 women undergoing IVF treatment, while follicular granulosa cells from unstimulated small antral follicles and corpus luteum were collected from 18 women undergoing ovarian tissue cryopreservation. Cells were cultured for up to 96 hours or 12 days with or without androstenedione or testosterone supplementation and analyzed using RT-qPCR and steroid hormone assays.

Results: In follicular granulosa cells, luteinization markers (CYP11A1, P < .05; STAR, P < .001) increased within 24 to 48 hours, while granulosa markers (HSD17β1, P < .001; CYP19A1, P < .05) decreased within 6 to 12 hours. Luteinizing hormone/choriogonadotropin receptor remained unchanged. By 48 hours, gene expression resembled that of the corpus luteum. In contrast, granulosa-lutein cells exhibited highly luteinized profiles from day 0, with significantly higher progesterone/(17)estradiol ratios. Androgen supplementation and long-term follicle-stimulating hormone exposure did not alter luteinization.

Conclusion: This study uniquely demonstrates that unstimulated follicular granulosa cells undergo a gradual, intrinsic luteinization process, independent of external hormonal triggers. In contrast, granulosa-lutein cells are already highly luteinized upon aspiration. These findings challenge conventional views on luteinization and highlight intrinsic cellular programming as a key driver, offering new insights into ovarian physiology and potential therapeutic targets for reproductive disorders.

Context: Transitioning from pediatric to adult-centered diabetes care may be challenging, especially for young individuals at risk for and with youth-onset type 2 diabetes (Y-T2D) who have a high disease burden and rapidly progressive disease. However, the scope of transition readiness, range of psychosocial factors, and perceived barriers among Y-T2D are understudied.

Objective: In Y-T2D attending an adult diabetes transition clinic, our objectives were to (1) characterize attitudes toward transition readiness, (2) examine relationships among depressive and anxiety-related symptoms and transition readiness, and (3) identify perceived barriers and facilitators of diabetes self-care.

Methods: Transition readiness was assessed with the Endocrine Society "Self-assessment of Worries, Concerns, and Burdens Related to Diabetes and Preparation for Transitioning," and mood symptoms with the Patient Health Questionnaire (PHQ-9), and the Generalized Anxiety Disorder (GAD-7) questionnaire. Logistic regression analyses evaluated the response to transition readiness by mood symptoms. Qualitative analysis identified themes of diabetes self-care in a subset of Y-T2D.

Results: Survey response rate was 89%; n = 65; age: 19.6 ± 2.0 years (mean ± SD); 85% Y-T2D; 15% prediabetes; 57% female; 78% Black; body mass index: 38.0 ± 8.2; and hemoglobin A1c: 7.6 ± 2.7%. Perceived challenges were reported in 95% of participants, and 54% reported worrying about their future. Mild or greater depressive and anxiety-related symptoms were associated with higher odds of reporting social, emotional, and cognitive challenges. Stress, socioeconomic difficulties, and challenges with organizational cognitive functioning were reported barriers to diabetes self-care.

Conclusion: Mood symptoms and difficulties with organizational cognitive functioning were commonly reported in Y-T2D during the transitioning period. Interventions are needed to successfully address these psychosocial factors.

Context: FK506-binding-protein-51 (FKBP51) is a glucocorticoid-induced co-chaperone protein previously shown to bind glucocorticoid receptor (GR), inhibiting its transcriptional activity. We previously found increased FKBP51 levels in uterine leiomyoma vs paired myometrium.

Objective: To test the hypothesis that elevated FKBP51 levels contribute to leiomyoma pathogenesis by altering GR signaling.

Design: RNA-sequencing was performed in leiomyoma cell cultures transfected with scramble or FKBP5-siRNA for 48 hours, then treated with vehicle or dexamethasone (DEX) for 24 hours. Differentially expressed genes, including HSD11B1, CNN1, and LAMA2 were analyzed by quantitative polymerase chain reaction. Hydroxysteroid 11-β dehydrogenase 1 (HSD11β1) expression was analyzed in leiomyoma, leiomyoma-adjacent paired myometrium, myometrium from patients without leiomyoma, and human endometrial stromal cells by quantitative polymerase chain reaction and immunohistochemistry.

Setting: University research institution.

Patients: Women with or without uterine leiomyoma.

Main outcome measures: HSD11B1 mRNA and protein levels in leiomyoma, paired myometrium, and normal myometrium.

Results: HSD11β1 expression was higher in paired myometrial and leiomyoma tissues vs normal myometrium (P < .02). DEX treatment increased HSD11B1 transcription in normal myometrial and human endometrial stromal cell cultures, but to a significantly greater extent in leiomyoma (P < .001). However, FKBP5-silencing blunted this DEX-induced HSD11B1 upregulation. DEX-treatment reduced LAMA2 and increased CNN1 levels (coding for extracellular matrix and smooth muscle proteins, respectively) in FKBP5-silenced vs scramble siRNA-transfected leiomyoma cultures.

Conclusion: FKBP51 not only inhibits but can augment GR-mediated transcription. Importantly, FKBP51-GR interactions increase HSD11B1 levels in leiomyoma cells, generating a pathological FKBP51-GR-HSD11β1 circle, altering transcription of downstream extracellular matrix and smooth muscle genes to induce a myofibroblast phenotype, thereby possibly contributing to leiomyoma pathogenesis.

Context: Thyrotropin (TSH) levels tend to rise with age, but standard reference intervals do not reflect this, potentially leading to overdiagnosis of subclinical hypothyroidism (SCH) and excessive levothyroxine (LT4) prescriptions in older adults.

Objective: This work aimed to compare outcomes in adults older than 50 years with SCH who were either prescribed or not prescribed LT4.

Methods: A retrospective cohort study was conducted using data from UK Primary Care patients from the Health Improvement Network. The primary outcome was cardiovascular (CV) events (angina, myocardial infarction, peripheral vascular disease, stent procedures, or stroke). Secondary outcomes included bone events (fragility fractures or osteoporosis) and all-cause mortality. Time-varying hazard ratios (HRs) adjusted for relevant factors were estimated.

Results: This study included 53 899 patients (baseline median age 67 years (interquartile range [IQR]: 59-76 years); 68.5% female; median TSH 4.6 mU/L (IQR: 4.1-5.4 mU/L). Median follow-up duration was 10 years (IQR: 5.5-10.0 years). Of these, 19 952 (37%) received LT4 and 33 947 (63%) did not. LT4 therapy showed a protective effect against CV events (HR: 0.91; 95% CI, 0.87-0.97; P < .001) but increased risk of bone events (HR: 1.21; 95% CI, 1.14-1.28; P < .001) and all-cause mortality (HR: 1.17; 95% CI, 1.13-1.22; P < .001).

Conclusion: Our data suggest that LT4 therapy in older individuals with SCH is associated with a trade-off between the potentially beneficial effect on CV risk and the deleterious relationship with bone health and mortality risk. These risks need to be considered, mitigated, and discussed when LT4 therapy is being deliberated in older patients with SCH.

Context: Short-statured midpubertal boys with predicted adult height (PAHt) below the third percentile are a therapeutic challenge. Aromatase inhibitors (AI) delay estrogen-driven epiphyseal fusion and possibly enhance adult height (AHt).

Objective: To assess the efficacy of AI treatment on AHt in midpubertal boys with a short PAHt due to advanced bone age (BA) or idiopathic short stature (ISS).

Design: Retrospective study.

Setting: Tertiary pediatric endocrine referral center.

Patients and methods: Two groups of midpubertal boys treated with AI were studied: 27 boys with fast puberty compared to matched untreated controls and 16 boys with ISS treated with GH and AI (GH&AI) compared to those treated with GH only. Anthropometric measurements, BA and PAHt, were tracked. AHt was compared across groups.

Main outcome measures: Achieved AHt in AI-treated boys vs controls and the PAHt.

Results: The median duration of AI treatment was 2.8 years for the AI-only group and 2 years for the GH&AI group. Throughout treatment, AI-treated groups gained height similarly to controls and showed a decrease in BA SD score (AI only: P = .009; GH&AI: P = .029) and an improvement in PAHt (AI only: P = .003; GH&AI: P = .037). Compared to controls, AI-treated children achieved greater AHt (AI only: 166.6 ± 3.1 cm vs 163.4 ± 1.3 cm, P = .003; GH&AI: 167.3 ± 6.1 cm vs 164.9 ± 3.5 cm, P = .194). The difference between AHt and PAHt at baseline was more pronounced in the AI-treated groups (AI only: 3.8 ± 3.5 cm vs -0.3 ± 5.0 cm, P = .001; GH&AI: 7.5 ± 5.2 cm vs 4.3 ± 3.6 cm, P = .050).

Conclusion: AI treatment extends the growth period, resulting in an AHt surpassing initial predictions. Our findings underscore the potential of AI treatment in midpubertal boys with a short PAHt due to advanced BA and in those treated with GH for ISS.

Context: INS-VNTR class I haplotype controls INS expression in thymus that might contribute to insulin tolerance induction.

Objective: We investigate the functional activities of differential tandem repeat units (TRUs) derived from insulin autoantibody-positive and -negative patients with type 1 diabetes (T1D).

Methods: INS-VNTR class I haplotypes derived from DNA samples from 28 gender-, age-, and human leukocyte antigen (HLA)-matched patients with T1D were polymerase chain reaction amplified and subcloned into pGL3-luciferase vector. The functional activities of the INS-VNTR locus were sequenced for composition and number of TRUs, measured INS-VNTR promoter activities, and AIRE binding capacity. Small molecules that enhance INS-VNTR-luc2 activity were identified.

Results: The mean TRUs (average from both alleles) were significantly longer in IAA- than IAA+ patients (39.8 vs 35.2). INS-VNTR promoter activity responds to the longer TRUs better than the shorter TRUs with AIRE, suggesting that longer TRUs exhibits stronger INS expression capacity potentially favorable for tolerance induction. The binding capacity of AIRE to confer INS transcription from various INS-VNTR haplotypes was determined via ChIP and pull-down assays. The INS-VNTR probe demonstrated differential binding affinity for the AIRE protein corresponding to TRUs, suggesting a differential INS expression in thymus. AIRE protein that binds to INS-VNTR could induce endogenous INS transcript in vitro. All-trans retinoic acid (vitamin A) is capable of stimulating INS-VNTR promoter activity, which provides a valuable option of early treatment of patients with prediabetes with daily vitamin A supplement.

Conclusion: Longer TRUs of the class I INS-VNTR haplotype favors INS expression in thymus and tolerance induction. Vitamin A supplementation could be beneficial for prevention of insulin autoimmunity at the early stages of T1D onset.